Abstract

Asthma is increasing in prevalence worldwide and results in significant use of healthcare resources. Although most patients
with asthma can be adequately treated with inhaled corticosteroids, an important number of patients require additional therapy
and an increasing number of options are available. A further minority of patients develop severe persistent asthma which remains
difficult to manage despite current pharmacological therapies. This review discusses the various treatment options currently
available for each stage of asthma severity, highlights some of the limitations of current management, and outlines directions
which may improve the management of asthma in the future.

Asthma is characterised by variable airflow obstruction, airway hyper-responsiveness, and chronic airway inflammation. It
is a common disease that can cause considerable morbidity and a significant mortality. Recent national and international asthma
management guidelines recommend a stepwise approach, with treatment increased until asthma control is achieved and stepped
down once control has been maintained for several months.1,2 Key factors required for good asthma control are outlined in box 1. Currently available anti-inflammatory and bronchodilator
drugs are very effective and good asthma control can be achieved for most patients. A significant minority, however, will
have more severe persistent asthma which is difficult to manage and which may necessitate alternative approaches. New drugs
which improve control for patients with severe disease, minimise side effects, or improve patient compliance are required.
Several new classes of treatment, which may fill these roles, are currently under investigation in asthma. We will review
the evidence supporting current asthma therapies including non-pharmacological treatments, suggest alternative approaches
where appropriate, and finally discuss novel classes of drugs which may be useful in the future management of asthma. We will
discuss the pharmacological options for each category of severity, which are defined in table 1. A summary of the main pharmacological
treatments for asthma at each stage of severity is given in box 2.

MILD INTERMITTENT ASTHMA

As required short acting β2-agonists

Inhaled short acting β2-agonists such as salbutamol and terbutaline are effective bronchodilators and should be prescribed to all patients with symptomatic
asthma.1,2 They are also useful in preventing symptoms of exercise induced asthma when given before the start of exercise,3 and are important in the treatment of acute severe asthma. Their mechanism of action is thought to occur primarily by the
relaxation of airway smooth muscle cells, but they also increase mucociliary clearance. They do not have any effective anti-inflammatory
activity. Although sympathomimetic agents, short acting β2-agonists have few side effects when inhaled, but tremor, palpitations, and tachycardia can occur with high doses. They should
be used for symptom relief on an as required basis, since studies have shown that their regular use provides no additional
benefit4,5 and may even be harmful. Furthermore, individual patients’ requirements for short acting β2-agonists provides a useful guide to the need for a step-up in treatment: current guidelines suggest that if they are used
on a daily basis for symptom control then regular anti-inflammatory agents are indicated.2 The use of more than one canister of short acting β2-agonists per month has been particularly associated with poorly controlled disease and should therefore alert the prescriber
to the need for increased regular anti-inflammatory treatment.6 Tolerance to the effects of short acting β2-agonists can occur, particularly to the protection against bronchoconstriction induced during indirect challenges.7

MILD PERSISTENT ASTHMA

Low dose inhaled corticosteroids

Corticosteroids are currently the most effective anti-inflammatory agents for the treatment of asthma and inhaled corticosteroids
are currently recommended for all patients with persistent asthma who require short acting β2-agonists more than once per day1 or those with intermittent asthma who experience severe exacerbations.2 They exert their anti-inflammatory effects through a diverse range of mechanisms including the activation of the glucocorticoid
receptor leading to the regulation of transcription of target genes, and the direct inhibition of a range of inflammatory
cells, particularly eosinophils. Studies have consistently shown that treatment with regular inhaled corticosteroids results
in significant improvements in airway inflammation in asthma, an effect demonstrated on bronchial biopsies8 and also on non-invasive markers of airway inflammation such as the differential eosinophil count in induced sputum or nitric
oxide concentrations in exhaled breath.9 Furthermore, there is evidence that corticosteroid treatment is not helpful in the absence of eosinophilic airway inflammation.10 In conjunction with these improvements in airway inflammation, inhaled corticosteroids improve symptoms,11 health status,12 airway hyper-responsiveness and lung function,13 and reduce asthma exacerbations.14 There is also epidemiological evidence from cohort and case-control studies showing that regular low dose inhaled corticosteroids
reduce both hospital admissions15 and asthma deaths.16 A recent study of patients with mild, apparently well controlled asthma showed that the addition of regular low dose inhaled
corticosteroids resulted in significant reductions in asthma exacerbations compared with placebo.14 These marked benefits, coupled with the low incidence of side effects, have led some to argue that inhaled corticosteroids
should be given to all but the mildest patients. It is not yet fully known whether long term treatment with inhaled corticosteroids
alters the natural history of the condition and protects against accelerated declines in lung function. A prospective study
of the effects of inhaled corticosteroids on pulmonary function showed that children who started inhaled corticosteroid treatment
more than five years after the onset of asthma had a significantly lower forced expiratory volume in one second (FEV1) than children who started treatment within two years of the diagnosis.17 In a placebo controlled trial in children with mild to moderate asthma, the use of regular inhaled corticosteroids over four
to six years resulted in improvements in symptoms, exacerbation rates and airway hyper-responsiveness compared with placebo,
but no differences in lung function.18 Further, long term prospective studies of the effects of regular inhaled corticosteroids on the decline in lung function
in adults are needed to address this important issue.

Side effects of inhaled corticosteroids

Patients are often concerned about the possibility of adverse effects of inhaled corticosteroids, and in some parts of the
world, notably North America, this has lead to their relative under-use. At low doses, up to 800 μg daily of beclomethasone
dipropionate or budesonide or 500 μg daily of fluticasone, systemic side effects are not usually significant, but do become
an issue at doses beyond this. Dysphonia commonly occurs due to deposition of inhaled corticosteroid particles locally in
the oropharynx19 and oral candidiasis may also develop.20 Systemic side effects include bruising and atrophy of the skin21 and reduced bone mineral density.22 Suppression of the adrenocortical axis can occur but this is not usually clinically significant.23 These systemic effects occur partly due to gastrointestinal absorption of swallowed particles and partly due to systemic
absorption via the airways. The use of spacer devices, dry powder mechanisms, and mouth rinsing after inhaler use minimise
adverse effects.24,25 Drugs with high first pass metabolism in the liver such as budesonide and fluticasone have fewer systemic side effects than
beclomethasone,26 but at high doses (>800–1000 μg daily of beclomethasone dipropionate/budesonide or >500 μg daily of fluticasone) systemic
absorption through the buccal and airway mucosa is an important consideration.

Cromones

The cromones sodium cromoglycate and nedocromil sodium, both given by inhalation, have been used as controller therapies in
mild persistent asthma.2 Their mechanism of action is not fully understood, although they are believed to suppress IgE-mediated inflammatory responses
and may inhibit inflammatory cells.27 Sodium cromoglycate has been shown to reduce symptoms and exacerbation frequency28 and nedocromil sodium to improve symptoms, lung function, and airway responsiveness.29 Overall, however, they appear to be rather less effective than low dose inhaled corticosteroids30 and their long term effects on airway inflammation are unknown. The use of these agents in adults has therefore largely been
superseded by the introduction of low doses of inhaled steroids for the majority of patients with persistent asthma.

MODERATE PERSISTENT ASTHMA

An important number of patients with asthma treated with low dose inhaled corticosteroids have sufficient symptoms to justify
an increase in treatment.31 The clinician is faced with an increasing number of treatment options for this important group of patients. Unfortunately
data from published placebo controlled studies of the different treatments are not always applicable to everyday clinical
practice in this area and important questions remain. We will therefore present the current evidence for each of the major
treatment options and briefly discuss some of the outstanding issues.

Long acting β2-agonists

Long acting β2-agonists (salmeterol and formoterol) are currently generally recommended as the first choice for patients who have symptoms
that persist despite regular inhaled corticosteroids. Salmeterol is a partial agonist of the β2-receptor while formoterol is a full agonist. Both appear to have similar clinical effects, but formoterol has a more rapid
onset of action.32 Side effects of tachycardia, tremor, and muscle cramps are rarely a problem unless given in high doses. Tolerance to the
effects of long acting β2-agonists with loss of bronchodilator activity after the subsequent administration of both short and long acting β2-agonists has been reported.33,34 As with short acting β2-agonists, these agents work primarily via the relaxation of airway smooth muscle, with additional effects on mast cells and
vascular permeability, but without significant anti-inflammatory activity.35 This lack of anti-inflammatory activity precludes their use as first line agents in asthma36 and current guidelines recommend that they are only prescribed alongside regular inhaled corticosteroids.1,2 When used in this way, long acting β2-agonists have been shown to improve day time and night time symptoms and the need for rescue β2-agonists.37,38 In a randomised controlled trial of 852 patients treated with low dose inhaled corticosteroids (the FACET study) the addition
of formoterol to inhaled low or high dose budesonide improved symptoms and lung function. In addition, the number of both
mild and severe asthma exacerbations was reduced, where mild exacerbations are defined as a fall in peak expiratory flow (PEF)
of >20% from baseline on two or more days, increased use of rescue short acting β2-agonists or nocturnal wakening and severe exacerbations defined as a fall in PEF of >30% from baseline on two or more days
or a deterioration in symptoms requiring rescue oral corticosteroids.39 This study also directly compared the addition of formoterol to the alternative strategy of increasing the dose of inhaled
corticosteroids. Compared with a fourfold increase in the dose of inhaled corticosteroids, the addition of formoterol resulted
in similar improvements in symptom control but smaller reductions in severe asthma exacerbations. In an uncontrolled study
of 429 patients with symptomatic asthma followed over six months, the addition of salmeterol to inhaled beclomethasone dipropionate
was shown to result in a greater increases in PEF and greater decreases in symptom scores than a 2.5-fold increase in the
dose of inhaled beclomethasone dipropionate, but no differences in exacerbations were seen.40 More recently, the OPTIMA study in patients with milder disease suggested that the addition of formoterol resulted in greater
reductions in exacerbation frequency than doubling the dose of inhaled corticosteroids.14 One important concern with long acting β2-agonists is that subjects recruited into many clinical trials are not fully representative of the patients we see in everyday
clinical practice. Many of the published studies, for example, only recruited patients who demonstrated acute improvements
FEV1 after inhaled bronchodilators of 15% or more.39–43 Such degrees of bronchodilator reversibility are distinctly unusual in clinical practice: only 28% of patients with asthma
in general practice demonstrated a 15% improvement in FEV1 after 2.5 mg nebulised salbutamol44 and only 5%–10% of patients with asthma in our clinic demonstrated similar increases in FEV1 after 200 μg inhaled salbutamol.45 Subjects therefore are not only atypical but are particularly likely to respond to bronchodilator therapy. There is a risk
that these studies are generalised to wider patient populations when a more reasonable interpretation is that long acting
β2-agonists are particularly helpful for a subgroup of patients who have marked bronchodilator response.

Increasing the dose of inhaled corticosteroids

The traditional approach to patients with persistent symptoms despite low doses of inhaled corticosteroids was to increase
the corticosteroid dose, but the evidence for this is somewhat inconsistent. While some studies have demonstrated clear dose
related improvements in symptoms and lung function,39,46,47 others have not demonstrated clinically important benefits with moderate or high doses.48 Overall the beneficial effects of increasing the dose of inhaled corticosteroids appear to be modest and may be largely outweighed
by the increased risk of side effects. As discussed earlier, the comparative studies have suggested that higher doses of inhaled
steroids are less effective at controlling symptoms and peak flow variability compared with the addition of long acting β2-agonists.39,40 While the relationship between improvement in symptoms and inhaled corticosteroid dose reaches a plateau, control of exacerbation
frequency is more closely related to inhaled corticosteroid dose. In the FACET study a fourfold increase in the dose of budesonide
resulted in a significantly greater reduction in the number of asthma exacerbations than the addition of formoterol.39 Conversely, a two-fold increase in the dose of budesonide did not result in similar improvements in the rates of exacerbations
in milder patients included in the OPTIMA study,14 suggesting that the higher dose ranges are required for the optimal prevention of exacerbations. There is increasing evidence
that asthma exacerbations are associated with eosinophilic airway inflammation,49,50 and the benefits of the high doses of inhaled corticosteroids on exacerbation frequency are therefore likely to reflect dose
related anti-inflammatory effects. Turner and colleagues have shown that a doubling of the dose of beclomethasone in subjects
with symptomatic asthma and a persistent sputum eosinophilia despite treatment with inhaled corticosteroids improved symptoms
and significantly reduced the sputum eosinophil count, whereas the addition of salmeterol led to improvements in symptoms
but no change in the sputum eosinophil count.50 Similarly, in a study of increasing doses of budesonide in patients with steroid naïve asthma, Jatakanon et al demonstrated a dose dependent reduction in the percentage of eosinophils in induced sputum.9 While low doses of inhaled corticosteroids are therefore probably appropriate for the majority of patients, higher doses
of these drugs may be indicated in some patients who experience frequent severe exacerbations of asthma or who have persistent
airway inflammation.

Leukotriene antagonists

Montelukast and zafirlukast are both effective cysteinyl leukotriene receptor antagonists capable of markedly inhibiting exercise
induced bronchoconstriction51,52 and the early and late response to inhaled allergen.53,54 When added to as required β2-agonists, clinical trials have shown improvement in lung function,41,42 reduction in the need for rescue bronchodilators,41,55 and some evidence of a reduction in eosinophilic airway inflammation.56 In the UK, leukotriene antagonists are currently licensed for use in patients who remain symptomatic despite treatment with
inhaled corticosteroids. Clinical trials have shown evidence of efficacy in patients taking high doses of inhaled steroids,43 and the introduction of montelukast has been shown to allow a reduction in the dose of inhaled corticosteroid without loss
of asthma control.57 The effectiveness of the addition of leukotriene antagonists compared with increasing the dose of inhaled corticosteroids
in patients with persistent symptoms, however, has not yet been fully addressed. Two studies published in abstract form comparing
zafirlukast with higher doses of inhaled corticosteroids did not show any important differences between the two treatment
strategies.58 A recent meta-analysis has suggested that the addition of leukotriene antagonists to inhaled corticosteroids does not significantly
reduce asthma exacerbations compared with increasing the dose of inhaled corticosteroids,59 but there is a paucity of adequately powered studies addressing this issue and further work is needed.60 The relative effectiveness of leukotriene antagonists compared with long acting β2-agonists as add-on therapy also remains unclear and needs further investigation.61 Although some studies have shown that the addition of long acting β2-agonists results in greater improvements in asthma control than the addition of leukotriene antagonists,62,63 others demonstrate that comparable improvements in symptoms and lung function are seen, with leukotriene antagonists providing
additional anti-inflammatory effects that long acting β2-agonists do not.64,65 It is possible that subgroups of patients with asthma may be particularly suited to treatment with leukotriene antagonists,
perhaps through genetic variations in the cysteinyl-leukotriene pathways (see below).

Theophylline

Theophylline has been used for many years in relatively high doses as a bronchodilator, but due to adverse effects it has
often been reserved for use in patients with more severe asthma. Gastrointestinal upset is particularly common66 but tachycardia and arrhythmia can also occur and measurements of serum concentrations are generally advised with high dose
treatment.2 Recent interest has been in the use of theophylline at lower doses where the risk of side effects is minimised. The combination
of low dose inhaled corticosteroids and theophylline has been shown to result in comparable asthma control as higher doses
of inhaled corticosteroids and may provide slightly greater improvements in lung function.67–69 A meta-analysis has suggested that long acting β2-agonists are more effective than theophylline in patients taking low doses of inhaled corticosteroids and result in fewer
side effects.70 Unlike long acting β2-agonists, however, theophylline has been shown to have possible anti-inflammatory activity and may therefore have a role
in some patients.71

SEVERE PERSISTENT ASTHMA

A proportion of patients will have persistent symptoms despite appropriate treatment for moderate persistent asthma as outline
above. While representing a relatively small minority, these patients experience much morbidity, consume significant healthcare
resources,72 and are probably best managed in specialist settings. Before additional therapeutic measures are considered it is important
to accurately confirm the diagnosis, to ensure that persistent symptoms are due to asthma rather than other aggravating factors
such as rhinitis or gastro-oesophageal reflux and to assess compliance with existing therapy. Once these issues have been
addressed current guidelines advocate a step-up in treatment, usually with high doses of inhaled corticosteroids in combination
with long acting β2-agonists, leukotriene antagonists, theophylline, oral β2-agonists, or a combination of these agents. There have been no randomised controlled studies comparing these different treatment
options in this group of patients and therefore additional therapy should be instituted on a trial basis and discontinued
if there is no objective evidence of benefit.12 Occasionally high doses of inhaled β2-agonists are needed for optimum symptom control. Though these may be administrated via a nebuliser, metered dose inhalers
used in combination with spacer devices have been shown to be equally effective even during acute exacerbations.73

Oral corticosteroids and corticosteroid sparing agents

A further group of patients have severe persistent asthma that remains difficult to control despite the measures outlined
above. In these circumstances treatment with oral corticosteroids, usually in the form of daily prednisolone, may be required
to minimise symptoms and prevent severe asthma exacerbations. While courses of oral corticosteroids are unquestionably a vital
part of the management of acute exacerbations, careful consideration should be made before they are administered on a long
term basis since there is a high risk of significant adverse effects.74 Where they are required, the lowest dose which maintains asthma control should be given. Preventative therapy for osteoporosis
should be considered and patients should be monitored for the development of hypertension, diabetes, cataracts, glaucoma,
and adrenal suppression. Obesity, thinning and bruising of the skin, and myopathy are also important concerns. High doses
of inhaled corticosteroids, up to 2 mg daily of beclomethasone or equivalent, should always be continued, as these are likely
to allow a reduction in the oral corticosteroid dose.75 Nebulised corticosteroids have not been shown to reduce systemic toxicity compared with equivalent doses of oral corticosteroids
and are not recommended.2 Other corticosteroid sparing agents include methotrexate, gold, and cyclosporin. Although there is some evidence that these
agents have steroid-sparing effects in asthma,76–78 each have their own safety concerns and their use should be confined to specialist units. The risk of adverse effects from
the use of long term oral corticosteroids and the lack of safe alternatives necessitates careful monitoring of the response
to treatment. A small minority of patients with severe asthma demonstrate resistance to corticosteroid treatment despite apparently
good compliance. The mechanisms for this resistance are not fully understood but may relate to transcriptional regulation
of genes associated with steroid responsive inflammation.79 These patients present a significant therapeutic challenge beyond the scope of this review.

NON-PHARMACOLOGICAL AND ALTERNATIVE THERAPIES IN ASTHMA

Smoking cessation

Cigarette smoking in adults with asthma is associated with an accelerated decline in lung function,80 increased symptom severity and exacerbation frequency,81 and an impaired response to inhaled corticosteroids.82 Although studies confined to populations of patients with asthma have not been done, smoking cessation clearly has a number
of important health benefits which are likely to be particularly important to patients with pre-existing respiratory disease.
Appropriate advice should therefore be given to all patients with asthma who smoke, and pharmacological treatments such as
nicotine replacement therapy or buproprion should also be considered.

Self management plans (personalised asthma action plans)

Combined with regular medical review, asthma self management plans, particularly those that include written advice for patients
to follow should symptoms and/or peak flow readings deteriorate, have been shown to reduce hospital admissions for asthma
and are recommended in current guidelines.1,83 Despite this, there have been some suggestions that neither patients nor primary health care professionals are convinced
of their benefits and they may be particularly suited to those patients with poor symptom perception or recurrent asthma exacerbations.84

Breathing retraining, Buteyko techniques, and physical training

There is increasing interest in breathing retraining techniques in asthma, particularly among patients and the lay press.
The Buteyko technique, for example, which uses hypoventilation in an attempt to raise the partial pressure of carbon dioxide
in the blood, has been advocated as a method to allow reductions in, or even withdrawal of, asthma medication. Unfortunately
rigorous trials of these methods have not yet been published and they should therefore be viewed with caution. It has recently
been recognised, however, that many patients treated for asthma in primary care also have symptoms suggestive of dysfunctional
breathing patterns.85 Results of a physiotherapy based breathing retraining programme in such patients suggested significant improvements in health
status in the short term,86 and more work in this area is clearly needed. It is likely that retraining techniques may improve symptoms and health status
where there is dysfunctional breathing, either in the context of mild asthma or where asthma has been misdiagnosed. Physical
training methods have been shown to improve cardiovascular fitness but not lung function in patients with asthma but effects
on symptoms and quality of life have not been assessed.87

Allergen avoidance

The exposure of patients with atopic asthma to the allergens that they are sensitised to has been shown to increase asthma
symptoms and airway hyper-responsiveness and to cause bronchoconstriction.88 Studies of measures that aim to control the exposure of house dust mite and pet allergens, however, have not conclusively
been shown to improve asthma outcomes and larger trials have been advocated.89 Studies of allergen control measures in infancy have shown reductions in respiratory symptoms,90,91 but it remains to be seen if such measures will prevent the development of atopy and asthma in later life.

Immunotherapy

Allergen specific immunotherapy, or desensitisation, involves the administration of specific allergen extracts via subcutaneous
injections of increasing concentration with the aim of inducing immunological tolerance. The process may work by generating
interleukin-10 producing regulatory T-cells. Immunotherapy appears to be particularly useful in allergic rhinitis but has
also been shown to improve symptoms and airway responsiveness in patients with allergic asthma.92 Overall the benefits appear to be modest, the technique is labour intensive, and major concerns about its safety remain since
life threatening anaphylactic reactions can occur. Thus, while some patients may gain dramatic benefits immunotherapy for
asthma is not recommended in the UK.93

FUTURE DEVELOPMENTS IN THE MANAGEMENT OF ASTHMA

It is likely that new therapies will become available over the next 5–10 years. Some of the more promising agents are discussed
below. We also feel that there will be increasing interest in the heterogeneous nature of asthma in the future, specifically
the heterogeneity of treatment response. Identification of factors predicting a response to treatment will enable therapy
to be targeted, may improve outcomes and result in more rational, economical use of treatment. This is likely to be particularly
important with the introduction of novel agents which are likely to be expensive, effective against only specific components
of a complex inflammatory cascade, and therefore best reserved for subgroups of patients most likely to respond. New developments
in the pharmacogenetics of asthma are likely to play a key role in this area.

(1) Novel pharmacological therapies

Anti-IgE monoclonal antibody

IgE has an important role in the development of allergic diseases in atopic subjects and suppression of IgE is therefore a
potential target in the management of atopic asthma. A monoclonal anti-IgE antibody, omalizumab, which blocks the interaction
of IgE with mast cells and basophils, has been developed. This has now been studied in patients with moderate and severe allergic
asthma treated with inhaled corticosteroids. Compared with placebo omalizumab, given as a subcutaneous injection at doses
titrated to serum IgE levels, it resulted in improved symptom control,94 fewer exacerbations, and greater reductions in inhaled corticosteroid doses with no apparent adverse effects.94,95 It therefore appears to be a potentially useful anti-inflammatory agent in patients with atopic asthma.

Monoclonal antibody to interleukin-5

Interleukin-5 is a very selective cytokine, which is responsible for the maturation and release of eosinophils in the bone
marrow. Since eosinophils are a characteristic pathological feature of asthma, inhibition of interleukin-5 represents another
potential treatment and two monoclonal antibodies to interleukin-5 are currently under investigation. The first published
study showed that the humanised anti-interleukin-5 monoclonal antibody SB-240563 was able to reduce the sputum eosinophilia
after allergen challenge when given intravenously, but had no effect on the early or late fall in FEV1, or on airway responsiveness.96 Since eosinophilic airway inflammation appears to be related more closely to asthma exacerbations than hyper-responsiveness,97 it is possible that agents such as anti-interleukin-5 will be more useful in preventing asthma exacerbations than minimising
day to day symptoms.

Humanised recombinant interleukin-12

Interleukin-12 is another potential treatment for asthma. It is a macrophage-derived cytokine that is able to suppress eosinophilic
inflammation via modulation of T-lymphocyte responses. A trial of subcutaneous humanised recombinant interleukin-12 given
to patients with mild asthma was somewhat disappointing. As with anti-interleukin-5, suppression of eosinophilic inflammation
occurred but was not associated with improvements in airway hyper-responsiveness.98 Additionally, significant side effects developed in a number of subjects and this is likely to limit its usefulness.

Interleukin-4 receptor antagonists

Interleukin-4 is another key cytokine in the development of airway inflammation that has been targeted in the search for novel
asthma therapies. A nebulised soluble interleukin-4 receptor which acts as an interleukin-4 antagonist is under investigation.
Initial studies have shown that this drug is well tolerated and may reverse the deterioration in symptoms and lung function
that occur after withdrawal of inhaled corticosteroids.99 Study withdrawal due to asthma exacerbations after corticosteroid withdrawal were not prevented, however, and larger studies
of longer duration are required.100

(2) Targeting the appropriate therapy for individual patients

It is becoming clear that the key features of asthma: symptoms, disordered airway function, airway inflammation, exacerbations
and long term decline in lung function, are not closely related to each other within patients and might have a different pathophysiological
basis. Recent studies have questioned a direct causal association between eosinophilic airway inflammation and airway hyper-responsiveness,96,97 and have suggested that infiltration of airway smooth muscle by mast cells might be more important.101 In contrast, asthma exacerbations are more closely related to eosinophilic airway inflammation, such that the induced sputum
eosinophil count has emerged as a good surrogate marker of exacerbation frequency.97 There is increasing evidence that some patients with asthma do not have eosinophilic airway inflammation and might not respond
to inhaled corticosteroids.10,97,102

Taken together, these findings suggest that targeting of treatment, based on assessments of the predominant feature of disease
in individual patients, might result in more effective use of treatment (table 2). It might also result in more economical
use of treatment compared with ad hoc treatment trials that are currently recommended. In a recent study we compared a management
strategy that aimed to normalise the induced sputum eosinophil count as well as minimise symptoms.97 We found that the sputum management strategy achieved significantly better control of eosinophilic airway inflammation and
a marked reduction in severe asthma exacerbations than the traditional management strategy (35 v 109, p=0.01). Furthermore, significantly fewer patients in the sputum management strategy were admitted to hospital with
asthma (1 v 6, p=0.047). There were no significant differences in the average daily dose of inhaled or oral corticosteroids between the
two groups, since monitoring airway inflammation in the sputum management strategy identified a group of patients whose sputum
eosinophil count was predominantly within the normal range. In these subjects we were able to markedly reduce the dose of
corticosteroids without evidence of deterioration in control. We have therefore shown that the use of induced sputum in targeting
anti-inflammatory treatment is feasible and results in significantly improved patient outcomes. In patients with moderate
to severe asthma at least, we believe that regular monitoring of airway inflammation in this way is required for optimal treatment.

Evidence for the efficacy of each class of treatment on the four major features of asthma

(3) Recent advances in the pharmacogenetics of asthma

Pharmacogenetics, the study of how genetic differences influence the variability of individual patient responses to drugs,
aims to distinguish responders from non-responders and thus lead to rationalised drug therapy. The clinical heterogeneity
of asthma has lead to increasing interest in the study of the genetic variability of this disease. There has been particular
interest in the pharmacogenetics of β2-agonists and modifiers of the cysteinyl-leukotriene pathway.

β2-Agonist pharmacogenetics

The cell surface β2-adrenergic receptor, via which β2-agonists exert their effects, contains a number of genetic variants. Single nucleotide polymorphisms resulting in amino acid
substitutions at positions 16 and 27 of the receptor and at position 19 of its upstream peptide are particularly common in
white populations and are related to each other.103,104 The role of these genetic polymorphisms in β2-agonist treatment response remains unclear, however. Some studies, for example, have suggested that the β2-adrenergic receptor position 16 genotype is associated with the response to β2-agonist treatment with Gly16 homozygotes having diminished and Arg16 homozygotes exaggerated treatment responses.105–107 Other studies, however have failed to demonstrate such an association.108,109 It is possible that combinations of different alleles (haplotypes) rather than single nucleotide polymorphisms are important
in determining treatment responses.

Leukotriene pharmacogenetics

Cysteinyl leukotrienes are important mediators in the inflammatory response in asthma. They are derived from arachidonic acid
via the 5-lipoxygenase pathway. The study of the pharmacogenetics of the leukotrienes has concentrated on two key enzymes
of this leukotriene synthesis pathway, 5-lipoxygenase and leukotriene-C4 synthase. 5-Lipoxygenase catalyses the conversion of arachidonic acid to leukotriene-A4 and is blocked by the drug Zileuton, which is not licensed in the UK.

An early study suggested that the response to a Zileuton derivative exhibited considerable genetically determined variability,
with patients who have two mutant alleles at the promoter sequence of the 5-lipoxygenase gene being resistant to treatment.110 The second key enzyme, leukotriene-C4 synthase is involved in the conversion of leukotriene-A4 to leukotriene-C4, which subsequently forms leukotriene-D4 and leukotriene-E4. The leukotriene receptor antagonists montelukast and zafirlukat inhibit the binding of these cysteinyl leukotrienes to their
receptor. Again, genetic polymorphisms of the leukotriene-C4 synthase gene may relate to variations in clinical response, with one study suggesting that patients with C/C and C/A variants
of the leukotriene-C4 synthase promoter respond particularly well to treatment with zafirlukast.111

Although clearly much more work is needed in this field, the study of pharmacogenetics offers great potential in furthering
our understanding of the heterogeneous nature of asthma and improving our use of existing asthma therapies. Such advancements,
which may enable the use of genotyping to tailor therapy for individual patients, are eagerly awaited.

CONCLUSIONS

Inhaled corticosteroids remain the cornerstone of treatment for patients with chronic asthma. While they effectively improve
eosinophilic airway inflammation and lung function and control asthma symptoms in most patients, a number will require additional
therapy. There is currently a range of effective additional treatments available for these patients. To rationalise the future
management of asthma it will be important to target treatments to those patients who are most likely to respond by identifying
individual treatment goals and carefully assessing the likely underlying pathophysiology. In patients with more severe asthma
close monitoring of airway inflammation is required for optimal management. Novel therapeutic agents which act on specific
components of the inflammatory pathway in asthma are emerging. The future management of patients with asthma may well involve
the use of these newer agents in combination with more established therapies.

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